Nutritional substrates include fats, proteins and sugars which are used for energy in the human body. The body stores excess energy until it is needed for energy production. Most of the long term storage is in the form of body fat. The balance between energy storage and energy utilization determines the fat content, a key component of body weight. The three components of energy expenditure are resting metabolism, physical activity and thermogenesis.
Oxygen is needed for the efficient cellular utilization of these energy stores and thermogenesis. Over 90% of cellular oxygen is consumed by mitochondria for the process of ATP formation, which is known as oxidative phosphorylation. Adenosine triphosphate (ATP) is the main high energy cellular substrate and is used for both cellular maintenance reactions (e.g., electrolyte balance and signal processing) and active processes (e.g., muscle contraction and protein synthesis).
The body is dependent upon mitochondrial oxidative phosphorylation for the efficient production of ATP. For example, for each molecule of glucose, 36 molecules of ATP are produced if mitochondrial oxidative phosphorylation is fully utilized whereas only 2 molecules of ATP are produced without mitochondrial processing.
Because ATP occupies such a central role in energy use/processing and due to the bodies dependence on mitochondria for the production of ATP, almost all nutritional substrates (including fats) are processed by cellular and mitochondrial enzymes (i.e., dehydrogenases) into the high energy electron carriers, NADH and FADH.sub.2. Each of these molecules delivers electrons to the respiratory chain of mitochondria located in the inner mitochondrial membrane. These electrons are passed down the respiratory chain and eventually placed onto oxygen via the enzyme cytochrome oxidase. As the electrons are passed down the respiratory chain, protons are extruded across the inner mitochondrial membrane which results in the formation of a proton gradient. The electrical and chemical energy of the proton gradient across the inner membrane is then used to create ATP in the process known as oxidative phosphorylation.
The body produces a substance that directly affects the efficiency of mitochondrial oxidative phosphorylation. This substance is known as thermogenin, which is a protein found in brown fat cells (so named due to the abundance of mitochondria in these cells). Thermogenin uncouples the production of ATP from electron transport and oxygen consumption. Thus, energy is consumed but is not utilized for energy production in these cells. Accordingly, uncoupling energy utilization from energy production could result in weight loss.
It has been found that patients with morbid obesity have less brown fat than patients of normal weight (see Himms-Hagen, Canadian J. Biochem. & Cell Biol., 62(7):610-617 (1984) and Santos, Arch. Path. & Lab. Med. 116(11):1152-1154 (1992)). Efforts to utilize the endogenous protein thermogenin to directly alter metabolism and body weight have not been successful, presumably due to low transport into cells and mitochondria. Other chemicals could potentially affect the efficiency of oxidative phosphorylation in a manner similar to thermogenin. However, most of these leads are proteins which are not easily absorbed after oral administration. Additionally, such agents are not well transported intracellularly as needed for biological activity.
Others efforts to chemically lower body weight by indirectly altering cellular energy metabolism have used hormones such as leptin and serotonin. These hormones are thought to indirectly alter the efficiency of energy metabolism and have not been demonstrated to have direct effects on oxidative metabolism. These hormones have other significant physiologic effects (e.g., elevated heart rate, elevated blood pressure, behavioral swings) beyond their effects on metabolism. Still further, some of these proposed mediators of obesity must be given parenterally.
What is needed in the art are new compositions and methods for controlling weight using safe agents which are readily absorbed after oral administration and which do not suffer the poor side effects and activity associated with the agents described above. Surprisingly, the present invention provides such compositions and methods.